ORCID

http://orcid.org/0000-0001-9639-366X

Date of Award

Spring 5-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Abnormalities in electrical impulse generation and/or propagation that affect the heartճ normal rhythm are extremely common. Clinically, cardiac arrhythmias are prevalent worldwide, yet the molecular mechanisms underlying their pathology remain largely unknown. Current treatments for arrhythmias primarily target symptoms rather than the underlying cause and these treatments have limited efficacy. The most common risk factor for developing an arrhythmia is a previous cardiac injury; however, the mechanisms underlying this are not well described. My thesis work has demonstrated that the Notch signaling pathway, which is crucial for cardiac patterning and development and is normally quiescent in adult cardiomyocytes (CMs), is reactivated in the adult heart following cardiac injuries that predispose to arrhythmias, such as myocardial infarction. Notch activation within the adult heart leads to changes in cardiac electrophysiology and gene expression in the right atrial (RA) chamber. We have shown that these chamber-specific changes persist even one year after a short pulse of Notch signaling activation, suggesting that even a small level of Notch signaling activation following cardiac injury is sufficient to cause long-term functional changes in cardiac electrophysiology. These mice develop conduction abnormalities akin to sick sinus syndrome (SSS) in humans, a disorder that predisposes an individual to atrial fibrillation (AF). Understanding molecular determinants in the pathogenesis of AF is crucial because it is the most common cardiac arrhythmia that affects up to 2% of the general population. AF represents a significant source of morbidity and mortality as it increases the risk of stroke and heart failure (HF). Current research has proposed that AF can be caused by multiple factors including genetics (such as mutations in coding or non-coding parts of the genome) and/or environmental factors (such as hypertension and diabetes). Past research has focused on genome-wide association studies to elucidate factors involved in AF; however, this limits our understanding of AF pathogenesis to genetic variation. In AF, triggers are believed to originate in the pulmonary veins (PVs) near the posterior left atrium (LA), and the LA itself is remodeled to create a substrate conducive for arrhythmia maintenance. My work found that Notch signaling is also re-activated in the LA following cardiac injury, suggesting Notch signaling may potentially be acting as an environmental factor that could predispose to AF. Based on my findings that Notch can cause changes to RA electrophysiology, I hypothesized Notch could also be causing electrophysiological changes in the LA. Traditionally, cardiac research has lumped ventricular chambers and atrial chambers together as similar units, but it is becoming increasingly clear that each cardiac chamber represents a distinct transcriptional unit that has a differential response to injury signals. Indeed, we characterized how Notch signaling electrically remodels the LA to predispose to AF and found that Notch signaling differentially affects ion channel gene expression in the RA versus the LA, even within the heart of the same mouse. Furthermore, cardiac electrophysiology of the RA shows an opposite phenotype than in the LA. Whereas Notch signaling affects Na+ channel gene expression and function by altering the Phase 0 of the action potential in the RA and therefore decreases CM excitability, K+ channel genes appear to be the main ion channels affected in the LA. Alterations to K+ channel genes leads to action potential duration (APD) prolongation, similar to the action potential phenotype seen in previously published work from the Moskowitz lab on a Tbx5 loss-of-function (LOF) mouse model of AF. Furthermore, RNA-sequencing performed by our lab on CM nuclei isolated from the LA of human AF patients revealed that Notch signaling is significantly upregulated compared to the LA of non-AF patients. Collectively, our findings demonstrate for the first time that activation of Notch signaling is associated with AF in both mouse models and human tissue, suggesting that Notch signaling is an environmental risk factor that can transiently turn on following cardiac injury. As a result, Notch activation leads to differential electrophysiological remodeling in the RA versus the LA and predisposes the heart to arrhythmias. Differential atrial remodeling could help explain why cardiac injury is the largest risk factor for developing an arrhythmia and could further explain why current treatments for arrhythmias are often ineffective and paradoxically pro-arrhythmic. Therefore, since each cardiac chamber has a differential response to injury, they should not be treated equally. In summary, my thesis work can be a blueprint for targeting arrhythmia treatments on individual chambers rather than treating the heart as a single unit. Furthermore, Notch signaling may be a potential target for inhibition following cardiac injury to prevent cardiac electrical remodeling and the development of potentially life-threatening arrhythmias.

Language

English (en)

Chair and Committee

Stacey L. Rentschler

Committee Members

Colin G. Nichols, David M. Ornitz, Richard B. Schuessler,

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